Cyclic guanosine 3′5′monophosphate (cGMP) is the common downstream second messenger of natriuretic peptides and nitric oxide. In cardiac myocytes, the physiological effects of cGMP are exerted through the activation of protein kinase G (PKG) signaling, and the activation and/or inhibition of phosphodiesterases (PDEs), providing an integration point between cAMP and cGMP signals. Specificity of cGMP signals is achieved through compartmentalization of cGMP synthesis by guanylate cyclases, and cGMP hydrolysis by PDEs. Increasing evidence suggests that cGMP-dependent signaling pathways play an important role in inhibiting cardiac remodeling, through the inhibition Ca²⁺ handling upstream of pathological Ca²⁺-dependent signaling pathways. Thus, enhancing cardiac myocyte cGMP signaling represents a promising therapeutic target for treatment of cardiovascular disease. This article is part of a Special Issue entitled “Local Signaling in Myocytes.”